Herbal Psychopharmacology
اسلاید 1: www.tabaye.ir
اسلاید 2: Herbal PsychopharmacologyJames W. Jefferson, MDClinical Professor of PsychiatryUniversity of Wisconsin SchoolOf Medicine and Public HealthRevised August 2007
اسلاید 3: Which of the following was responsible for herbal products “flooding” the U.S. market in recent years?A.Federal Food, Drug and Cosmetic ActB.Kefauver-Harris AmendmentC.Dietary Supplement Health and Education ActD.Nutrition Labeling and Education ActE.Food and Drug Modernization Act
اسلاید 4: 2.Which of the following has been most closely associated with hepatotoxicity?A.GinkgoB.KavaC.Saw palmettoD.St. John’s wortE.Valerian
اسلاید 5: 3.Which of the following is the clinically most important effect of St. John’s wort on the cytochrome P450 (CYP) system?A.1A2 inhibitionB.2D6 inhibitionC.2C9 inductionD.2E1 inductionE.3A4 induction
اسلاید 6: 4.St. John’s wort has been most extensively studied for the treatment of which of the following disorders?A.BipolarB.Posttraumatic stressC.PanicD.Major depressiveE.Social anxiety
اسلاید 7: 5.A placebo-controlled, double-blind study found Ginkgo biloba to be ineffective for treating antidepressant-induced sexual dysfunction.A.TrueB.False
اسلاید 8: ObjectivesUnderstand the ramifications of DSHEAAppreciate the current efficacy status of herbals for treating psychiatric disordersBe aware of the potential effects of herbals on drug metabolism
اسلاید 9: OutlineHistorical Overview – DSHEA and its RamificationsValerianA.Clinical StudiesB.Drug InteractionsGinkgoA.Clinical StudiesB.Drug InteractionsC.Bleeding
اسلاید 10: Outline (Cont’d.)KavaA.Clinical StudiesB.HepatotoxicityC.Drug InteractionsSt. John’s WortA.Clinical StudiesB.Mechanism of ActionC.Side EffectsD.Drug Interactions
اسلاید 11: Outline (Cont’d.)VI.Other HerbalsA.UsesB.Drug InteractionsVII.JuicesA.GrapefruitB.OrangeC.PomegranateVIII.Resources
اسلاید 12: Historical overviewDSHEA (1994)Clinical efficacyDrug interactionsWords of warning
اسلاید 13: Herbs and plants are medical jewels gracing the woods, fields and lanes which few eyes see, and few minds understand. Through this want of observation and knowledge the world suffers immense lossLinnaeus 1707-1778
اسلاید 14: Progress?1938: Food, Drug and Cosmetic Act Proof of safety1962: Kefauver-Harris AmendmentProof of efficacyRequired reporting of adverse events1994: Dietary Supplement Health and Education Act (DSHEA)(sponsored by Senator Orrin Hatch, signed by President Clinton)
اسلاید 15: Dietary Supplement Healthand Education Act (1994)Removed supplements from food additive regulationsBurden of proof on FDANo federal regs for purity, etc.No mandatory reporting of AEs
اسلاید 16: Since then, these products have flooded the market, subject only to the scruples of their manufacturers.Angell and Kassirer, NEJM 9/17/98
اسلاید 17: “In the United States, the public spends almost $4 billion yearly on supplements, with little or no data on what they can expect.”Lewis and Strom. Ann Int Med 136:617-618, 2002In 2003, Americans spent nineteen billion dollars on dietary supplementsSpecter M. The New Yorker, Feb 2, 2004, pp 64-75
اسلاید 18: 50 Ginseng PreparationsAnalyzed for ginsenosides Content varied from 1.9% to 9% (4.7 fold difference) 6 (12%) had noneCui et al: Lancet 7/9/94
اسلاید 19: Asian Patent Medicines from California Herbal StoresUndeclared pharmaceuticals – ephedrine, chlorphenarimine, methyltestosterone, phenacetinHeavy metal contamination - lead, arsenic, mercury32% of 260 medicinesCalifornia Dept. of Health Services, NEJM 9/17/98
اسلاید 20: Tongkat Ali Power Plus: A Natural Remedy to Improve Sexual Health and Libido“Our products are natural herbal powder made in a more convenient-to-use form capsules” Analysis of 15 capsules found sildenafil, 59 mg/capsule. 10 of the 15 also contained tadalafil, 1.4 mg/capsuleKenyon et al. J Clin Pharmacology 2006;46:1379-1381BUT
اسلاید 21: FDA Issues Dietary Supplements Final RuleTo require good manufacturing practices (GMPs) for supplementsTo ensure quality production, no contaminants, accurate labelingEffective August 24, 2007, but with a long phase-inDoes not address efficacy and safety issueshttp://www.fda.gov
اسلاید 22: Valerian(Valeriana officinalis)
اسلاید 23: Valerian(Valeriana officinalis)Galen - the Phu plant (dried roots stink)U.S. Pharmacopoeia 1820-1942 (the 19th century Valium)WWII - for shell shockRat-catchers baitCats-ecstasy
اسلاید 24: Valerian in PsychiatryInsomniaBetter than placebo in 6/7 double-blind studiesSlow onset (2-3 weeks)AnxietyOnly open-label reportsWell tolerated (mild hangover?)Does odor defeat the blind?Krystal and Ressler. CNS Spectrums 10/01
اسلاید 25: Valerian for InsomniaInternet-based, 4-week, double-blind, placebo-controlled6.4 mg valerenic acids hs (odor masked)Valerian (n=135) = placebo (n=135)Jacobs et al., Medicine 2005;84:197-207
اسلاید 26: Valerian for Insomnia: Systematic Review and Meta-Analysis16 randomized, placebo-controlled trials, N=1093Methodologic problems in most, and preparations, doses, durations varied considerably“The available evidence suggests that valerian might improve sleep quality”Better studies are needed Bent et al. Am J Medicine 2006;119:1005-1012
اسلاید 27: Valerian-Drug Interactions (14 days, healthy vol., n=12)No clinically significant effects on CYP2D6 (dextromethorphan) or 3A4 (alprazolam)Alprazolam Cmax 20% (AUC, T1/2 unchanged)Donovan et al. Drug Metab Dispos 2004;32:1333-1336
اسلاید 28: Valerian and CYP450 Inhibition (28 days, healthy subjects, n=12)No significant effect CYP1A2, 2D6, 2E1, 3A4Gurley et al., Clin Pharmacol Ther 2005;77:415-426
اسلاید 29: Valerian and CYP450 InhibitionSo far, so goodClinical studies-very limited data -only in 24 healthy volunteers
اسلاید 30: Ginkgo (Ginkgo biloba)
اسلاید 31: Ginkgo Biloba Tree(Maidenhair Tree)Oldest living tree species (200 million years)Lives up to 1000 yearsGrows up to 122 feetDurable -only tree to survive Hiroshima -popular in NYC
اسلاید 32: Ginkgo Biloba ComponentsFlavonal glycosidesKaempferolQuerectinIsorhamnetinMyricetinTerpene lactonesGinkgolidesBilobalideEtc.
اسلاید 33: Ginkgo Biloba for DementiaInconsistent dataFurther research neededCholinesterase inhibitors preferredKurz and Van Baelen, Dement Geriatr Cogn Disord 2004;18:217-226Diamond et al., Drugs Aging 2003;20:981-998
اسلاید 34: Extract of Ginkgo Biloba in DementiaGERRIPlaceboEGb ImprovedLe Bars et al: JAMA 278:1327-1332, 1997
اسلاید 35: Ginkgo Biloba vs. Placebo on Cognitive Performance in Multiple Sclerosis 12-week, double-blind, n=38Dose: 120 mg twice dailyResults: Overall, no statistically significant improvement in cognitive functionLovera et al. Multiple Sclerosis 2007;13:376-385
اسلاید 36: Ginkgo/Ginseng Combination and Cognitive FunctionHealthy, middle aged volunteers (n=256)14 week, double-blind, placeboSignificant improvement on Index of Memory Quality (7.5%)Wesnes et al. NCDEU Poster 81, June 2000
اسلاید 37: Ginkgo for Memory Enhancement (6 week, double-blind, n = 230)Volunteers, over 60 years old40 mg t.id. versus placeboNo benefit, but well toleratedSolomon et. al. JAMA 288:835-840, 2002
اسلاید 38: Ginkgo Biloba: No Robust effect on Cognitive Abilities or Mood in Healthy Young or Older Adults12-week, double-blind, placebo-controlled, n=93 older, n=104 young adultsDose: 120 mg/dayBurns et al. Human Psychopharmacol Clin Exp 2006;21:27-37
اسلاید 39: Ginkgo Biloba Extract EGb 761 for Generalized Anxiety Disorder (n=82) and Adjustment Disorder with Anxious Mood (n=25)4-week, double-blind, placebo-controlledDose: 240 mg or 480 mg/dayResults (HAM-A ): EGb 761 > placebo (both doses)Response: 480 mg 44%, 240 mg, 37%, placebo 22%Woelk et al. J Psychiatric Research 2007;41:472-480
اسلاید 40: Ginkgo Biloba for Antidepressant–Induced Sexual Dysfunction (n=37)240 mg/day EGb761 vs. placebo8 week, double-blindIneffective!Kang et al. Human Psychopharmacol 2002;17:279-284
اسلاید 41: Ginkgo Biloba-Drug InteractionsDonepezil (2D6, 3A4 substrate)*30-days, 90 mg/day, n=14no effectNifedipine (3A4 substrate)**simultaneous, single dose, n=12no effect overallblood levels doubled in 2Omeprazole (2C19, 3A4 substrate)***12-day, 280 mg/day, n=18CYP2C19 induction ~ 58% AUC *Yasui-Furukori et al., J Clin Pharmacol 2004;44:538-542 **Yoshioka et al., Biol Pharm Bull 2004;27:2006-2009***Yin et al., Pharmacogenetics 2004;14:841-850
اسلاید 42: Ginkgo Biloba-Drug Interactions (28-day, normal vol., n=12)Dose: 60 mg qidNo effect on phenotypic ratios: CYP1A2, 2D6, 2E1, 3A4Gurley et al., Clin Pharmacol Ther 2002;72:276-287
اسلاید 43: Ginkgo Biloba-Drug Interactions (14-day, normal volunteers, n=12)Dose: 120mg bid (EGb 761)2D6 (dextromethorphan)no effect3A4 (alprazolam)17% AUCMarkowitz et al., J Clin Psychopharmacol 2003;23:576-581
اسلاید 44: Ginkgo Biloba Effects on 2C9 and 3A4 (14-day, normal volunteers, n=10)Dose: 360 mg/day (EGb 761) for 28 days2C9 (tolbutamide): 16% AUC3A4 (midazolam): 25% AUCStatistically significant, but clinical significance unclearUchida et al. J Clin Pharmacol 2006;46:1290-1298
اسلاید 45: Ginkgo Biloba and CYP450 Small in vivo studies in humans—induction of 2C19, little or no effect on 1A2, 2D6, 2E1, 3A4 (small sample sizes)In vitro inhibition of 1A2, 2C9, 3A4 but only by certain constituentsRat data do not extrapolate well to humans
اسلاید 46: Ginkgo Biloba and BleedingSubdural hematoma (2 cases)Subarachnoid hemorrhage (1 case)Intracerebral bleed (1 case)Vitreous hemorrhage (1 case)Spontaneous hyphema (1 case)Avoid with aspirin, NSAIDS, valproate, warfarin, etc.
اسلاید 47: Kava(Piper methysticum)
اسلاید 48: KavaPiper methysticum(intoxicating pepper)South Pacific ceremonial and social drinkA stress and anxiety reducing herbal superstar?
اسلاید 49: Kava DrinkingIt gives a pleasant, warm andcheerful, but lazy feeling, sociable,though not hilarious or loquacious;the reason is not obscured.Hocart, 1929
اسلاید 50: Kava (Piper methysticum)Properties - anxiolytic/sedative - muscle relaxant - analgesic - anticonvulsantComponents (kavalactones) - methysticin - kavain - dihydrokavain - and others
اسلاید 51: Kava for AnxietyEffective in 7 double-blind studiesMeta-analysis of 3 studies -Kava > placebo by 10 points on HAM-APittler and Ernst. J Clin Psychopharmacol Feb 2000
اسلاید 52: Kava for GAD at Duke (4 week, double-blind, n = 35)Kava Pure (140 mg 280 mg Kl/day)Kava = Placebo on all measuresHigh Anxiety: Placebo > KavaLow Anxiety: Kava > PlaceboConnor and Davidson. Int Clin Psychopharm 17:185-188, 2002
اسلاید 53: Kava for Generalized Anxiety Disorder (pooled analysis of 3 small, double-blind, placebo-controlled studies)Sample: Kava, n=28, placebo, n=30, venlafaxine XR, n=6Dose: 140 mg 280 mg kavalactones/day)Results: Kava not effective (significant effects favored placebo) Connor et al Int Clin Psychopharmacol 2006;21:249-253
اسلاید 54: Kava for AnxietyInternet-based, 4-week, double-blind, placebo-controlled100 mg total kavalactones tidKava (n=121) = placebo (n=135)Jacobs et al., Medicine 2005;84:197-207
اسلاید 55: Kava Hepatotoxicity78 cases associated with kava (causal ?)11 liver transplants4 deathsJan 2003-banned in European Union, Canada; FDA advisory in USMechanism: drug interaction ?, glutathione ?, extraction method?, idiosyncrasy ????Clouatre DL. Toxicol Lett 2004;150:85-96
اسلاید 56: Kava and CYP450 Inhibition (28 days, healthy subjects, n=12)CYP2E1 – 40% inhibitionCYP1A2 – no effectCYP2D6 – no effectCYP3A4 – no effectGurley et al., Clin Pharmacol Ther 2005;77:415-426
اسلاید 57: Chronic Kava Drinkers Abstain for 30 days (n=6)Caffeine metabolic ratio doubledProbes for 2C19, 2D6, 2E1, 3A4 not affectedKava drinking inhibits 1A2Russmann et al., Clin Pharmacol Ther 2005;77:453-454
اسلاید 58: Kava-Drug InteractionsCYP450 potency similar to grapefruit juice? (3A4 inhibition in vitro, but not in vivo)Potentiation of CNS-depressants (ALP/Kava coma)Antiplatelet activityMAO-B inhibitionNo clinical drug interaction studies thus farAnke and Ramzan, J Ethnopharmacol 2004;93:153-168
اسلاید 59: St. Johns Wort(Hypericum perforatum)
اسلاید 60: Bioactive Constituents ofSaint Johns WortPhenylpropanesFlavonol glycosidesBioflavonesProanthocyanidinsXanthonesPhloroglucinols (hyperforins)Naphthodianthrones (hypericins)Nahrstedt and Butterweck: Pharmacopsychiat 30:129-134, 1997
اسلاید 61: St. John’s Wort for Depression (meta-analysis of double-blind studies)Versus placebo – 27 studies MDD – minimal benefit Non-MDD – possible benefitVersus standard antidepressant – 14 studies – similar efficacy“Current evidence…is inconsistent and confusing”Linde et al. Br J Psychiatry 2005;186:99-107
اسلاید 62: SJW vs Sertraline and Placebo in MDD (8 week, double-blind, n=340)*Entry:HAM-D17 20Dose:SJW 900-1500 mg (mean max 1299 mg) Sertraline 50-100 mg (mean max 75 mg)Response:SJW=sertraline=placebo on both primary outcome measuresDavidson et al. JAMA 2002;287:1807-1814 *NCCAM and NIMH funded
اسلاید 63: St. John’s Wort vs. Sertraline and Placebo in MDD (A Research Surprise)Detectable plasma hyperforinSJW group: negative in 17%Placebo group: positive in 17%Did not influence overall outcomeVitiello et al., J Clin Psychopharmacol 2005;25:243-249
اسلاید 64: St. John’s Wort for Depression - 2005Moderate Depressive Disorder (n=241)* “Not inferior to sertraline”Major Depression (n=251)** “At least as effective as paroxetine”Major Depression (n=163)*** SJW = fluoxetine = placebo Mild-Mod MDD (n=135)**** *Gastpar et al., Pharmacopsychiatry 2005;38:78-86 **Szegedi et al., Br Med J 2005;330:503-506***Bjerkenstedt et al., Eur Arch Psychiatry Clin Neurosci 2005;225:40-47****Fava et al., J Clin Psychopharmacol 2005;25:441-447 (Oct)SJW > fluoxetine; SJW trend> PBO
اسلاید 65: St. John’s Wort for Depression: Cochrane Database Review, Feb 25, 2005Total of 37 trials, 26 compared to placebo, 14 to standard antidepressants“current best evidence from placebo comparisons shows only minor benefits of hypericum in patients with major depression”Current evidence is inconsistent and confusing Linde et al. Cochrane Database of Systematic Reviews, published online April 20, 2005
اسلاید 66: Hypericum Extract STW3-VI vs Citalopram and Placebo in MDD (6-week, double-blind, n=388)Entry:HAM-D17 20-24Dose:Extract 900 mg/day Citalopram 20 mg/dayEfficacy (HAM-D ): Extract=Citalopram>placebo* Response: Extract 52%, citalopram 56%, placebo 39%Gastpar et al. Pharmacopsychiatry 2006;39:66-75 *p<0.0001
اسلاید 67: St. Johns WortMechanisms of Action ?5-HT, NE, DA uptake inhibition (equipotent)GABA receptor bindingMAO inhibition - very weakProtein kinase C inhibitionInterleukin-6 suppressionNMDA-receptor antagonism
اسلاید 68: Hyperforin in Rat Locus Coeruleus Increases ExtracellularSerotoninNorepinephrineDopamineGlutamateKaehler et al: Neuroscience Letters 20:199-202, 1999
اسلاید 69: St. John’s Wort, Antidepressant Drugs and the Elderly5 patients (ages 64 to 84) sertraline (4), nefazodone (1)2-4 days on SJW nausea (5), vomiting (3), anxiety (3), restlessness (2), epigastric pain (1), confusion (1)Serotonin syndrome?Lantz et al. J Geriatr Psychiatry Neurol 12:7-10, 1999
اسلاید 70: Hypericin in HIV-Infected Adults (i.v. or p.o., n=30)No antiviral activitySevere phototoxicity 48%Gulick et al: Ann Int Med 130:510-514, 1999
اسلاید 71: “I now have several anecdotal reports of (St. John’s wort) causing breakthrough bleeding in women on (oral contraceptives)” C. Cracchiolo: Currents Affect Illness 17:11, 1998
اسلاید 72: St. John’s Wort and BC PillsInduces ethinyl estradiol and norethindrone metabolism breakthrough bleedingReports of unplanned pregnancyHall et al., Clin Pharmacol Ther 2003;74:525-535
اسلاید 73: St. John’s Wort/Drug InteractionsCYP 1A2 – Induced (?)CYP 2B6 – InducedCYP 2C9, 2C19--InducedCYP 2E1 – InducedCYP 3A4 – Induced (esp. intestinal)P-Glycoprotein – Induced(Initial Inhibition)
اسلاید 74: P-GlycoproteinA transmembrane efflux pumpLocated in intestine, liver, kidney, brainDecreases drug absorption, increases drug secretionChemotherapy resistant cancer cells
اسلاید 75: Pregnane X Receptor (PXR)Nuclear receptorActivated by diverse xenobioticsStimulates transcription of CYP3A and P-glycoprotein genesActivated by hyperforin, but not by hypericinMoore et al., Proc Nat Acad Sci 2000;97:7500-7502
اسلاید 76: St. John’s Wort and DigoxinInduction of P-glycoproteinDigoxin Cmax 37%, AUC 25% (Hyperforin-rich preparation)Marked variability with dose and formulationMueller et al., Clin Pharmacol Ther 2004;75:546-557
اسلاید 77: St. John’s Wort Increases Warfarin Clearance S-warfarin (2C9) R-warfarin (1A2, 3A4) INR (international normalized ratio Anticoagulant effectJiang et al., Br J Clin Pharmacol 2004;57:592-599
اسلاید 78: St. John’s Wort and AlprazolamSJW - 300 mg tid for 14 daysAlprazolam - 2 mg single doseAlprazolam (CYP3A4 substrate) AUC x 2 Clearance x 2 T1/2 12.4 6.0 hoursMarkowitz et al., JAMA 2003;290:1500-1504
اسلاید 79: St. John’s Wort and Carbamazepine (Healthy volunteers, n=8)CBZ x 14 days, CBZ + SJW (300 mg tid) x 14 daysNo change in CBZ clearanceWhy?? (CBZ induces SJW?)Burstein et al., Clin Pharmacol Ther 2000;68:605-612
اسلاید 80: Eich-Höchi et al., Pharmacopsychiatry 2003;36:35-37St. John’s Wort and Methadone (CYP3A4 substrate)
اسلاید 81: HMG-CoA Reductase Inhibitors (Statins) 3A4 2C19 non-P450Atorvastatin*FluvastatinPravastatin(Cervistatin*) 2C9Lovastatin RosuvastatinSimvastatin*Active metabolites
اسلاید 82: St. John’s Wort and Statins (n=16 healthy males, double-blind, placebo-controlled)Simvastatin (3A4) - AUC about 50%Pravastatin (non-P450) – no changeSugimoto et al., Clin Pharmacol Ther 2001;70:518-524
اسلاید 83:
اسلاید 84: Effect of St. John’s Wort on Cyclosporine Blood LevelRuschhitzka et al. Lancet. 2000;355:548-549Time (Month/Year)Time (Month/Year)Cyclosporine (g/L)Cyclosporine (g/L)3002001000Heart transplantationHypericin (900 g/3times daily)Apr 98Feb 99Mar 99Apr 99May 993002001000Jul 97Feb 99Mar 99Apr 99May 99Heart transplantationHypericin (900 g/3 times daily)
اسلاید 85: St. John’s Wort Decreases Cyclosporine Blood Levels in Kidney Transplant Patients (n=30)Mean trough level 47%Range of decrease 33-62%Breidenbach et al. Transplantation 5/27/00
اسلاید 86: Hyperforin and Cyclosporine AUC (renal transplant patients, n=10)St. John’s Wort 900 mg/dayHigh HYF 52%Low HYF No changeMai et al., Clin Pharmacol Ther 2004;76:330-340
اسلاید 87: Hyperforin Content in SJW (8 Commercial Preparations)Range: 0.01% to 1.89%*A 189-fold difference!De Los Reyes and Koda. Am J Health-Syst Pharm 2002;59:545-547*It was 3.1% in the US sertraline/placebo study
اسلاید 88: St. John’s Wort CYP3A Induction Varies From Product to ProductLinked to hyperforin (HYF) contentMidazolam (CYP3A substrate) AUC decreased 79%- HYF 41 mg/day 48%- HYF 12 mg/day 21%- HYF 0.13 mg/day Mueller et al. Eur J Clin Pharmacol 2006;62:29-36Madabushi et al. Eur J Clin Pharmacol 2006;62:225-233
اسلاید 89: Odds and Ends
اسلاید 90: Saw Palmetto (Serenoa repens)Prostate healthHealthy subjects (14 days, n=12) CYP2D6 – no effect CYP3A4 – no effectMarkowitz et al., Clin Pharmacol Ther 2003;74:536-542
اسلاید 91: GinsengsAmerican (Panax quinquefolius)* Warfarin level and effectAsian (Panax ginseng)** No effect – 1A2, 2D6, 2E1, 3A4Siberian (Eleutheroccus senticosus) No effect – 2D6, 3A4*** digoxin level (n=1)**** *Yuan et al., Ann Intern Med 2004;141:23-27 **Anderson et al., J Clin Pharmacol 2003;43:643-648 ***Donovan et al., Drug Metab Dispos 2003;31-519-522****McRae S., Can Med Assoc J 1996;155:293-295
اسلاید 92: Milk Thistle (Silybum marianum)GI, liver, gall bladder problemsHuman hepotocyte culture* CYP3A4 – inhibition UGT– inhibitionHealthy subjects (n=10)** Indinavir (3A4) – no effect *Venkataramanan et al., Drug Metab Dispos 2000;28:1270-1273**Piscitelli et al., Pharmacotherapy 2002;22:551-556
اسلاید 93: Echinacea purpurea (coughs, colds, bronchitis, etc) (12 healthy subjects)CYP1A2 – inhibitionCYP2C9 – little effectCYP2D6 – no effectCYP3A intestinal – inhibition hepatic - inductionOrski et al., Clin Pharmacol Ther 2004;75:89-100
اسلاید 94: Garlic (Allium sativum L.) (14 healthy subjects, 14 days)Antibacterial, antiparasitic, antilipidemic, antihypertensive, immunostimulantDextromethorphan (CYP2D6)No changeAlprazolam (CYP3A4)No changeMarkowitz et al., Clin Pharmacol Ther 2003;74:170-177
اسلاید 95: Garlic (10 healthy subjects, 39 days)Saquinavir (CYP3A4) AUC 51%P-glycoprotein induction?Piscitelli et al., Clin Infect Dis 2002;34:234-238
اسلاید 96: Angelica dahuricaChinese herbal – allergy and coldInhibits metabolism (rats)tolbutamide (2C)nifedipine (3A)bufurol (2D1)testosterone (2C11)Ishihara et al., J Pharm Pharmacol 2000;52:1023-1029
اسلاید 97: Goldenseal (Hydrastis canadensis)“A cure-all type herb”28 days, healthy subjects, n=12 CYP2D6 – strong inhibition CYP3A4 – strong inhibitionGurley et al., Clin Pharmacol Ther 2005;77:415-426
اسلاید 98: FastOne Dietary SupplementKola nut, grape, green tea, ginkgo bilobaCYP1A2 induced ~200% in 3 days in humans (n=4)more potent than smokingcarcinogenic potential?Ryn and Chung, Food and Chemical Toxicol 2003;41:861-866
اسلاید 99: And Now the Juices
اسلاید 100: Grapefruit JuiceInhibits CYP3A4 (gut wall), 1A2, 2A6, 2B6Cyclosporine levels 300%Lovastatin peak conc. 12-foldFelodpine peak conc. 500% (bp and rate effects double)Saquinavir AUC 220%
اسلاید 101: Buspirone and Grapefruit JuiceTime (hr)Buspirone (ng/ml)Lilja et al. Clin Pharmacol Ther 12/98Buspirone + GFJBuspironeCYP3A4
اسلاید 102: Grapefruit Juice Also InhibitsP-glycoprotein (P-gp)Organic Anion-Transporting Polypeptide (OATP) -A and -B(as does orange juice, but less potent)Satoh et al., Drug Metab Dispos 2005;33:518-523,2005
اسلاید 103: Seville (Sour) Orange JuiceIt does inhibit CYP3A4, but apparently not P-glycoproteinPenzak et al. J Clin Pharmacology 2001:41:1059-1063
اسلاید 104: Orange Juice Decreases Atenolol Absorption (n=10 volunteers)200 ml tid – juice or waterCmax 49%, AUC 40%Inhibition of OATP?Lilja et al., Eur J clin Pharmacol 2005;61:337-340
اسلاید 105: Pomegranate Juice (Punica granatum)Rats: intestinal 3A inhibition Carbamazepine AUC x 1.5Human liver microsomes: CPY2C9 inhibitionHuman volunteers: No effect on CYP3A activity (midazolam clearance)Hidaka et al., Drug Metab Disp 2005;33:644-648Nagata et al. Dug Metab Distribution 2007;35:302-305Farkas et al. J Clin Pharmacology 2007;47:286-294
اسلاید 106: PDR for Herbal Medicines 4th edition, 2007 Thomson Healthcare
اسلاید 107: Alternative Medicine Foundation www.amfoundation.orgEvidence based research resource for professionalsReliable consumer informationHerbMed– interactive evidence-based herbal formulary
اسلاید 108: QuackWatch www.quackwatch.com
اسلاید 109: Which of the following was responsible for herbal products “flooding” the U.S. market in recent years?A.Federal Food, Drug and Cosmetic ActB.Kefauver-Harris AmendmentC.Dietary Supplement Health and Education ActD.Nutrition Labeling and Education ActE.Food and Drug Modernization Act
اسلاید 110: 2.Which of the following has been most closely associated with hepatotoxicity?A.GinkgoB.KavaC.Saw palmettoD.St. John’s wortE.Valerian
اسلاید 111: 3.Which of the following is the clinically most important effect of St. John’s wort on the cytochrome P450 (CYP) system?A.1A2 inhibitionB.2D6 inhibitionC.2C9 inductionD.2E1 inductionE.3A4 induction
اسلاید 112: 4.St. John’s wort has been most extensively studied for the treatment of which of the following disorders?A.BipolarB.Posttraumatic stressC.PanicD.Major depressiveE.Social anxiety
اسلاید 113: 5.A placebo-controlled, double-blind study found Ginkgo biloba to be ineffective for treating antidepressant-induced sexual dysfunction.A.TrueB.False
اسلاید 114: ConclusionsLimited, often conflicting, clinical data (best with St. John’s wort)Marked variability in active ingredientsOften undeclared ingredientsMore regulation necessaryMore research necessary
اسلاید 115: Answers to Pre & Post Lecture ExamsCBEDA
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